Given the importance of autophagy as a cell survival and resistance pathway, understanding and unlocking a key autophagic target could lead to an innovative approach to abrogate drug resistance. The goal of this project is to develop p62 as a more optimal approach to inhibit autophagy, and provide a rapid path to enter clinical trials for therapeutic drug development using the prototype agent verteporfin, a drug that inhibits p62 and is approved by FDA to treat macular degeneration. Although autophagy is considered a target for resistance to initial androgen axis-targeting therapies in prostate cancer, existing approaches to target autophagy (hydroxychloroquine (HCQ) for example) with collateral induction of p62 may be a reason for suboptimal results. Using a genetically engineered mouse model, we showed that autophagy-related-7 (Atg7)-deficiency delayed Pten-deficient prostate tumor progression in both castrate-nave and castrate-resistant cancers, demonstrating the potential of autophagy as a therapeutic target, although with associated induction of p62. To further optimize this approach, we targeted p62 using the prototype agent verteporfin, as it is known to inhibit p62 by formation of crosslinked p62, leading to inhibition of autophagy. Our preliminary studies show that verteporfin inhibited prostate cancer cell growth, decreased p62, and generated crosslinked p62 oligomer, resulting in inhibition of constitutive activation of Nrf2 and its target proteins, leading to reduced apoptosis resistance. In normal prostate epithelial cells, elevation of p62 is sufficient to cause constitutive Nrf2 activation, apoptosis resistance, and tumorigenesis. Verteporfin inhibited tumorigenesis of both p62-exprssing prostate epithelial cells and prostate cancer cells. The central hypothesis is that inhibition of p62 is a more effective approach to target autophagy; that verteporfin can be developed as a therapeutic against prostate cancer by inhibiting p62, autophagy, and Nrf2 signaling, a drug resistance pathway; and that the combination of verteporfin with other therapies, such as docetaxel, HCQ, or ADT, reduces prostate cancer growth and progression in a synergistic or additive manner. Aim 1 will determine if verteporfin decreases constitutive activation of Nrf2 and downstream pathways through inhibition of p62, leading to decreased apoptosis resistance and tumorigenesis. Aim 2 will further determine if verteporfin and/or p62-deficiency (a) results in delayed Pten-deficient prostate cancer growth and enhanced Atg7-deficiency-caused delay in Pten-deficient prostate cancer growth in both castrate-nave and castrate-resistant cancers; (b) inhibits autophagy; (c) decreases constitutive Nrf2 activation and its downstream pathways; and (d) reduces the androgen receptor pathway. Aim 3 will investigate the effect of verteporfin in combination with docetaxel or HCQ to better design clinical trials with greater likelihood of impacting synergy with known standard approaches including combination therapies with docetaxel or hormonal agents. Successful completion of these studies will result in the development of new therapeutic approaches against prostate cancer through inhibition of p62.